Bile acids and bile acid derivatives are useful in the treatment and prevention of diseases. Bile acids have been shown to induce internalization of the TGR5 fusion protein from the cell membrane to the cytoplasm (Kawamata et al., 2003, J. Biol. Chem. 278, 9435). TGR5 is associated with the intracellular accumulation of cAMP and is an attractive target for the treatment of diseases (e.g., obesity, diabetes and metabolic syndrome). Numerous bile acid derivatives are TGR5 agonists, capable of regulating TGR5-mediated diseases and conditions. For example, 23-alkyl-substituted and 6,23-dialkyl-substituted derivatives of chenodeoxycholic acid (CDCA), such as 6α-ethyl-23(S)-methyl-chenodeoxycholic acid, have been reported as potent and selective agonists of TGR5 (Gioiello, et al., 2012, Exp. Opin. Ther. Pat. 22, 1399, Pellicciari, et al., 2007, J. Med. Chem. 50, 4265, and Pellicciari, et al., 2009, J. Med. Chem. 52, 7958).
Additionally, a number of bile acid derivatives are Farnesoid X receptor (FXR) agonists, and are able to regulate FXR-mediated diseases and conditions (Gioiello, et al., 2014 Curr. Top. Med. Chem. 14, 2159). FXR is a nuclear receptor that functions as a bile acid sensor controlling bile acid homeostasis. FXR is expressed in various organs and shown to be involved in many diseases and conditions, such as liver diseases, lung diseases, renal diseases, intestinal diseases, and heart diseases, and biological processes, including glucose metabolism, insulin metabolism, and lipid metabolism.
Bile acids are often isolated from mammalian and microbial organisms that naturally produce them. However, bile acids isolated from such organisms may contain toxins and contaminants. Moreover, methods of preparing bile acid derivatives by using microorganisms can lead to contamination of the final product. Thus, there are needs for synthetic methods of producing bile acids free of all moieties of animal origin and of pyrogenic moieties. The present application addresses these needs.